Solid, hydrophobic lubricants continue to be currently used in the pharmaceutical art of tableting and filling of hard gelatin capsules even though it is known that the use of hydrophobic lubricants such as magnesium stearate diminish dissolution rates, and consequently could possibly reduce absorption rates, of the dosage formulation. Diminished dissolution rates of several capsule formulations with increases of magnesium stearate concentration were disclosed by Samyn and Jung, J. Pharm. Sci. 59, 169 (1970). Iranloye et al., J. Pharm. Sci. 67, 535 (1978), studied the effects of concentration of hydrophobic lubricants (calcium stearate, glyceryl monostearate, magnesium stearate, stearic acid and talc) on the dissolution rate of salicylic acid, aspirin and equimolar mixtures thereof and reported decreased dissolution rates with increased concentration of each lubricant other than talc. The authors concluded that, if hydrophobic lubricants slow dissolution, highly water-soluble lubricants might enhance dissolution. However, polyethylene glycol 4000 failed to affect dissolution at concentrations as high as 5 percent, leading the authors to speculate that the lubricant must simultaneously be water-soluble and surface active to enhance dissolution. Levy et al., J. Pharm. Sci. 52, 1139 (1963 ), had previously shown that sodium lauryl sulfate increased dissolution rates of salicylic acid over that of magnesium stearate in compressed tablets.
The use of surfactants in pharmaceutical formulations to assist in disintegration and dissolution of drug material is well known. Lachman et al., Theory and Practice of Industrial Pharmacy, Second Edition, pp. 108-9, disclose the use of surface active agents or surfactants in almost every dosage form including liquids, semi-solids and solids. The surface active agents play an important role in the absorption and efficacy of certain drugs. The nature of this role is quite obscure. Both enhancement of absorption and retardation of drug absorption have been credited to the presence of surface active agents. It cannot always be determined whether the function of a surfactant is to alter solubility, dissolution rates, and/or absorbability of the drug based upon its action on the drug itself or on a semi-permeable membrane within the host body. Similarly, whether the formation of micelle units and their polar/non-polar molecule orientation is critical to the function of the surfactants is not readily ascertainable.
Chiou et al., J. Pharm. Sci. 65, 1702 (1976), disclose enhanced dissolution rates for poorly water soluble drugs by crystallization from an aqueous surfactant solution. Polysorbate 80 (Tween 80) was employed in 2.5% aqueous solution for the purpose of drug precipitation.
Lerk et al., J. Pharm. Sci. 67, 935 (1978), disclose hydrophilic coating of hydrophobic drug particles to enhance wetting and dissolution. Hersh, U.S. Pat. No. 3,927,196, had shown earlier that a hydrophobic lubricant could be coated with a hydrophilic material to enhance dissolution of a therapeutic composition containing the lubricant.
Goodhart et al., J. Pharm. Sci. 62, 304 (1973), disclose a method for testing tablet and capsule dissolution rates. The authors note that previous studies have demonstrated prolonged disintegration/dissolution times with an increase in the level of magnesium stearate which is the standard lubricant employed in hard gelatin capsule formulations. The magnesium stearate in effect waterproofs the contents of a hard gelatin capsule. The authors noted on page 308, that the addition of a surfactant such as sodium lauryl sulfate improved disintegration of the capsules when tested in artificial gastric fluid without enzymes.
Short et al., J. Pharm. Sci. 61, 1733 (1972), disclose the dissolution of hydrocortisone in a number of systems containing an N-alkylpolyoxyethylene surfactant.
U.S. Pat. No. 3,862,311 granted Jan. 21, 1975, to Leeson, discloses the use of various types of surfactants in conjunction with polyethylene glycol carriers for assistance in dissolution and absorption of compositions containing progesterone. The preferred surfactants are non-ionics.
Geneidi et al., J. Pharm. Sci. 67, 114 (1978), disclose the theoretical relationship between enhancement of dissolution rate of a drug and its GI absorption rate.